Influenza Vaccination Coverage in Children: How Has COVID-19 Influenced It? A Review of Five Seasons (2018–2023) in Central Catalonia, Spain

Influenza vaccination is the main method of preventing influenza. Vaccination is recommended for certain individuals with diseases that could cause complications in the case of flu infection. The objective of this retrospective observational study was to examine influenza vaccination coverage in patients with risk factors, to describe the characteristics of those vaccinated and to study the influence of COVID-19. The study population was children under 14 years old with risk factors between 2018/19 and 2022/23 in Central Catalonia, sourced through the electronic database of the Catalan Institute of Health. The association of influenza vaccination data with sociodemographic data and risk factors was performed by bivariate and multivariate analysis. A total of 13,137 children were studied. Of those, 4623 had received the influenza vaccine in at least one season. The average influenza vaccination rate was 28.8%. The statistically significant factors associated with vaccination were age and having certain risk factors: asthma, diabetes, haemoglobinopathies and clotting disorders. In all seasons, the immigrant population was vaccinated more than the native population p < 0.05, except for the COVID-19 season (2020/21), where no differences were observed. Of those vaccinated, 7.1% had been vaccinated for 5 consecutive years. Influenza vaccination coverage in the paediatric age group was low. Vaccination promotion measures must be implemented. COVID-19 meant an increase in vaccination of the native population to the same level as that of the immigrant population.


Introduction
Seasonal influenza is a disease with a major public health impact [1,2].The World Health Organization (WHO) estimates that the annual influenza epidemic causes 1 billion infections, 3-5 million cases of severe disease and 290,000-650,000 deaths [1,3].Children seem to be the most affected by this infection [4] and are the main transmitters of the virus [3].In Spain, the highest cumulative incidence rate for influenza in the last two seasons (2021/22-2022/23) was observed in the 0-4 age group, followed by the 5-14 age group [5,6].Influenza hospitalisations in the same period were highest in the elderly, followed by the 0-4 years age group [5,6].
Vaccination is the best way to prevent influenza [4].In Catalonia (a region located in north-eastern Spain), up to the 2022/23 season, the Department of Health recommended influenza vaccination for all children between 6 months and 14 years of age with any condition at risk of suffering complications due to influenza virus infection [Table 1] as well as children from 6 months old who live with a person with any at-risk pathology [7].Epidemiological studies suggest that 1 in 4 children have a chronic disease, with prevalence figures varying between 10 and 30% and, among them, asthma stands out as the main pathology with a prevalence of between 7 and 15% in Spain [8].Obesity shows a generalised increasing trend in developed countries; in Europe it is a particularly serious problem in the countries of the South [8].
On the other hand, the COVID-19 pandemic, since its onset in December 2019, led to a reduction in routine childhood vaccination coverage worldwide [16][17][18][19][20].The arrival of the pandemic caused a disruption in health services around the world, and Spain was no exception.Containment measures, the closure of health centres and the suspension of essential activities hindered access to health services, including vaccination programs, especially for the most vulnerable groups such as children under 2 years of age.In addition, fear of SARS-CoV-2 infection and uncertainty led to the increased reluctance of some parents to go to health centres to vaccinate their children with routine vaccines [18].
Childhood influenza vaccination coverage during the COVID-19 pandemic varied by country [21][22][23][24][25][26][27][28][29][30].In the United States, for example, most studies report a decrease in influenza vaccination coverage [21,22,26,27].As for the rest of the Americas, most countries also experienced a decrease in the percentage of influenza vaccination during 2020 [23].Only Chile, Colombia and Peru experienced an increase in influenza vaccination coverage in children during the COVID-19 pandemic.South Korea, China and Italy also reported an increase in childhood influenza vaccination coverage [24, [28][29][30].As for Spain, no publications or data on the subject have been found.
The main objectives of this study were to describe childhood influenza vaccination coverage in Central Catalonia (Spain), to analyse the variables associated with vaccination, to study adherence to vaccination in children with risk factors in the last five seasons (2018-2023) and to evaluate the effect of the COVID-19 pandemic on childhood influenza vaccination.

Study Design and Participants
This was a retrospective observational study conducted in the healthcare district of Central Catalonia (Spain).
The study included all children between 6 months and 14 years old with any risk factor [Table 1] for receiving the influenza vaccination and who were assigned to a primary care centre in Central Catalonia.This area provides healthcare to approximately 502,000 people.The number of children registered in this region is about 623,000.Data were collected for the last five seasons (2018/19 to 2022/23).These data were obtained from the electronic database of the Catalan health system (Catalan Institute of Health).

Variables
The variables analysed for each patient were as follows: age, sex, level of education of the mother and father, place of residence (rural or urban), place of origin (Spain or other), risk factors for receiving the influenza vaccination, number of risk factors for receiving the influenza vaccination, influenza vaccination status and adherence to influenza vaccination; influenza vaccination was the independent variable and the remaining variables were the dependent variables.
To classify the place of residence in rural or urban area, we considered the number of people living in the village.A rural area is an area with fewer than 10,000 inhabitants.An urban area is an area with more than 10,000 inhabitants.
The risk factors described in Table 1 were grouped into 10 categories: asthma, heart disease, coeliac disease, diabetes, haemoglobinopathies and clotting disorders, immunosuppression and neoplasms, neuromuscular and neurological diseases, chromosomopathies and metabolopathies, nephropathies and hepatopathies, obesity and miscellaneous.
Complete adherence was defined as having been vaccinated against influenza consecutively each year throughout the study period.For the calculation of this variable, children who could not have been vaccinated during 5 consecutive seasons due to their age were excluded.
To assess the effect of the COVID-19 pandemic on childhood influenza vaccination, the different variables studied and associated with vaccination were related to each vaccination season separately.If any variable was statistically significant or no longer statistically significant during the seasons coinciding with the COVID-19 outbreak, we considered whether COVID-19 had any effect on influenza vaccination in children.

Statistical Analysis
A descriptive and comparative analysis of the characteristics of vaccinated and unvaccinated children with risk factors from the 5 study seasons was performed and expressed as percentages, and a statistical significance of 95% was used.To calculate influenza vaccination coverage, children with risk factors who had been vaccinated against influenza were compared with all children who could have been vaccinated, i.e., all children aged 6 months to 14 years who had any condition putting them at risk and who were eligible for influenza vaccination.The average influenza vaccination coverage for the five seasons and for each season were calculated.
To analyse the connection between the different variables and vaccination, a bivariate and multivariate analysis was performed.In the bivariate analysis, the Odds Ratio and its 95% confidence interval are shown and used, and in the multivariate analysis, the data were adjusted in a logistic regression.The selection criteria for the variables for the multivariate analysis for each season were as follows: that the data were statistically significant in the bivariate analysis in the last season, presence in more than 1% of the population and the clinical criteria of the researchers.
Finally, for the calculation of vaccination adherence, the sum of the seasons that each child had received the influenza vaccine was calculated.If the sum was equal to 5, it was considered correct adherence.If the sum was less than 5, it was considered incorrect adherence.
All differences were examined using confidence intervals and a confidence level of 95% was established.A p < 0.05 was considered statistically significant.
Statistical analyses were performed with program R version 4.2.1 (R Foundation for Statistical Computing).

Influenza Vaccination Coverage in Children
The mean influenza vaccination coverage over the 5 years of the study was 28.8%  3].

Variables Associated with Influenza Vaccination
Table 4 shows the association of the different variables with influenza vaccination by season using bivariate and multivariate analysis.We observed that the variables age, number of risk factors and some of the risk factors such as asthma and diabetes were positively and statistically significantly associated with influenza vaccination in all seasons.Heart disease, coeliac disease and obesity were negatively associated with influenza vaccination in seasons, such that patients with these three conditions were statistically significantly less vaccinated against influenza.
In all seasons, it was observed that the younger the children, the more they were vaccinated.
The variables country of origin and haemoglobinopathies and clotting disorders are discussed in the following section because of the influence that COVID-19 had on influenza vaccination in these groups.
We observed that the variable "country of origin" is statistically significant in the pre-COVID-19 seasons, but that during the 2020/21 season (considered to be the first season of the COVID-19 pandemic) it is no longer associated with influenza vaccination in a statistically significant way.After this season, this variable returns to statistical significance, but only in the multivariate analysis.That is, before and after the COVID-19 pandemic, immigrant children were the most vaccinated against influenza, but during the pandemic, the vaccination of native children increased to equal that of immigrant children [Table 4].

Adherence to Influenza Vaccination
Of the 4623 children vaccinated over the five seasons studied, 49% of the children had been vaccinated in only one season, 21.6% in two seasons, 15.2% in three seasons, 7.2% in four seasons and 7.1% in all five seasons studied.Therefore, only 7.1% of vaccinated children had complete adherence to the influenza vaccination.children were vaccinated at the same rate as immigrants.The main reason for this change may be fear of COVID-19.
Asthma, diabetes, haemoglobinopathies and clotting disorders were the risk factors most associated with vaccination.Asthma is one of the most prevalent childhood diseases [43] with a high risk of complications and emergency department and hospital visits.Diabetes is a chronic disease that involves a lot of tests, which makes families experience it as a serious pathology.All this could explain why vaccination is more common in these groups.The increased rate of vaccination in patients with haemoglobinopathies and clotting disorders may be related to vaccination in immigrant children, since most of the children in this group had sickle cell disease, a disorder that more frequently affects certain minority ethnic groups from sub-Saharan Africa, India, Saudi Arabia and some countries in the Mediterranean area [44].As for the number of risk factors, there is a positive relationship between vaccination and having more risk factors.This is logical since the more risk factors, the greater the risk of complications from the influenza virus.Heart disease, coeliac disease and obesity were negatively associated with vaccination in our study.In the case of coeliac disease and obesity it may be due to the lack of a sense of illness on the part of the family and the patient themselves.In the case of heart disease, poor vaccination is a cause for concern, and we found no explanation to justify it.
Finally, adherence to influenza vaccination in children in the different seasons is low in relation to the objectives proposed by the Catalan Department of Health.Most children were vaccinated in one season only (49%) and only 7.1% were vaccinated throughout the five seasons.Díaz-García R et al. found 65.9% adherence during the 2018/19 season and the following two seasons [4].
This study has limitations, the most important of which is that, since it is a descriptive study, it does not allow us to establish causal relationships between variables, but we can establish hypotheses.Another limitation is that we have only included children assigned to the ICS because we do not have information on children vaccinated by other health care providers or those covered by private insurance.In any case, the ICS provides health care for most of the children in our area, so the data are representative of our population.
As strong points, it should be noted that this is the first study of the effect of COVID-19 on childhood influenza vaccination coverage in Spain.This study was carried out in children with risk factors.
One line of research could be to observe whether immigrants of different races and from different countries have the same predisposition to vaccinate children against influenza.

Conclusions
Influenza vaccination coverage in children with risk factors in Central Catalonia is low, as is adherence to the influenza vaccination.It is necessary to change vaccination policies to improve coverage and adherence to vaccination in children.Some risk factors such as asthma, diabetes, and haemoglobinopathies and clotting disorders are associated with vaccination.Influenza vaccination is higher in immigrant children than in native children.
The COVID-19 pandemic positively influenced influenza vaccination in children, as vaccination coverage was higher and native children were vaccinated at the same rate as immigrant children.

Institutional Review Board Statement:
The study was conducted in accordance with the Declaration of Helsinki, and approved by the IDIAP Jordi Gol ethics Committee (code 23-/139.Date of approval: 26 July 2023).
Informed Consent Statement: Not applicable.Data were anonymous.

Table 1 .
Risk factors that the Catalan Department of Health considered as indications for receiving the influenza vaccine in children older than 6 months up to the 2022/23 season.
-Disorders and diseases that entail cognitive dysfunction: Down's syndrome, etc. -Children and adolescents receiving prolonged treatment with acetylsalicylic acid, due to the possibility of developing Reye's syndrome after influenza.-Long-term institutionalised children.-Children between 6 months and 2 years old with a history of prematurity, born at less than 32 weeks gestation.

Table 2 .
Demographic and clinical characteristics of vaccinated and unvaccinated infants with risk factors for receiving influenza vaccination between 6 months and 14 years.

Table 3 .
Number of vaccinated children and seasonal influenza vaccination coverage.

Table 4 .
Associated variables with seasonal influenza vaccination.Bivariate and multivariate analysis.
* Reference: to not have the risk factor.BV: Bivariate analysis.MV: Multivariate analysis.